A severe upper respiratory tract syndrome caused by the new coronavirus has now spread to the entire world as a highly contagious pandemic. The large scale explosion of the disease is conventionally traced back to January of this year in the Chinese province of Hubei, the wet markets of the principal city of Wuhan being assumed to have been the specific causative locus of the sudden explosion of the infection. A number of findings that are now coming to light show that this interpretation of the origin and history of the pandemic is overly simplified. A number of variants of the coronavirus would in principle have had the ability to initiate the pandemic well before January of this year. However, even if the COVID-19 had become, so to say, ready, conditions in the local environment would have had to prevail to induce the loss of the biodiversity’s “dilution effect” that kept the virus under control, favoring its spillover from its bat reservoir to the human target. In the absence of these appropriate conditions only abortive attempts to initiate the pandemic could possibly occur: a number of them did indeed occur in China, and probably elsewhere as well. These conditions were unfortunately present at the wet marked in Wuhan at the end of last year.

1049 Background: HER2 is an effective therapeutic target for breast and gastric cancer. A166 is an antibody-drug conjugate composed of a novel cytotoxic drug site-specifically conjugated to transtuzumab sequence via a stable protease-cleavable valine citrulline linker. Methods: This was a single arm, open-label, multicenter, dose escalating Phase 1 first-in-human study of A166 as monotherapy in solid tumor patients. Dose escalation and MTD identification was directed using a Bayesian logistic regression model with overdose control. The following dose levels were evaluated in this study: 0.3, 1.2, 3.6, 4.8 mg/kg. (ClinicalTrials.gov NCT03602079) Results: As of November 1, 2019 35 pts have completed the DLT evaluation period across 4 dose levels. Overall, A166 had an acceptable toxicity profile with no unexpected toxicities related to the study drug. No adverse events recorded met the protocol specified definition of a dose limiting toxicity at any studied dose level. Most frequently (≥10%) occurring TEAEs include were Keratitis, Decreased appetite, Dry eye, Vision blurred etc. Overall incidence of ophthalmic toxicities in the 3.6 mg/kg cohort was 80% and in the 4.8 mg/kg cohort it was 83%. Among the 27 patients evaluable for efficacy, best response was progression of disease in 11 patients (41%), stable disease in 9 patients (33%) and partial response in 7 patients (26%), for the total disease control rate of 59%.Responses were seen only at the dose levels of 3.6 mg/kg and 4.8 mg/kg. Conclusions: A166 demonstrated clinically meaningful efficacy in heavily pretreated patients with relapsed or refractory advanced solid cancers. The achievement of an ORR of 36% at efficacious dose levels and up to 100% in HER2 positive patients regardless of histology (2 CRC, 1 BC and 1 NSCLC) at the highest studied dose level exceed Clinical trial information: NCT03602079 .

Myeloid-derived suppressor cells (MDSCs) play an important role in tumor immune escape. Recent studies have shown that MDSCs contribute to tumor progression under psychological stress, but the underlying mechanism of MDSCs mobilization and recruitment remains largely unknown. In the present study, a chronic restraint stress paradigm was applied to the H22 hepatocellular carcinoma (HCC) bearing mice to mimic the psychological stress. We observed that chronic restraint stress significantly promoted HCC growth, as well as the mobilization of MDSCs to spleen and tumor sites from bone marrow. Meanwhile, chronic restraint stress enhanced the expression of C-X-C motif chemokine receptor 2 (CXCR2) and pErk1/2 in bone marrow MDSCs, together with elevated chemokine (C-X-C motif) ligand 5 (CXCL5) expression in tumor tissues. In vitro, the treatments of MDSCs with epinephrine (EPI) and norepinephrine (NE) but not corticosterone (CORT)-treated H22 conditioned medium obviously inhibited T-cell proliferation, as well as enhanced CXCR2 expression and extracellular signal-regulated kinase (Erk) phosphorylation. In vivo, β-adrenergic blockade with propranolol almost completely reversed the accelerated tumor growth induced by chronic restraint stress and inactivated CXCL5-CXCR2-Erk signaling pathway. Our findings support the crucial role of β-adrenergic signaling cascade in the mobilization and recruitment of MDSCs under chronic restraint stress.

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TPS3659 Background: Elevated expression of trophoblast antigen 2 (TROP2) is often associated with invasion/aggression, progression, and metastasis of many different tumor types. Efficacies of anti-TROP2 ADC have been demonstrated both pre-clinically and in the clinical trials. SKB264 is being developed as a further optimized TROP2-targeting ADC with a proprietary cytotoxic, belotecan-derived payload and novel stable conjugation chemistry to achieve average DAR (Drug Antibody Ratio) of 7.4. Release of payload upon SKB264 internalization is in a TROP2 expression dependent manner. Extensive preclinical studies demonstrated antitumor activity of SKB264 in vitro, in xenograft and patient-derived xenograft (PDX) animal models. In addition, safety studies have demonstrated a good safety profile to allow SKB264 to be studied in clinical trials. Methods: SKB264-01 is a global open label multicenter study. The study is divided into 2 parts, the phase I is to determine the safety profile, define MTD and/or the RP2D, and characterize DLTs of SKB264. Dose escalation and MTD identification will be directed using a Bayesian logistic regression model (BLRM) with overdose control. The phase II is to evaluate efficacy and obtain clinical activity data of SKB264 as a monotherapeutic agent at the RP2D in each of the designated Phase II cohorts and overall (n = 16 per cohort; n = 48 for entire Phase II part). Objective response rate (ORR) will be continuously evaluated in each cohort using a Bayesian hierarchical model. TROP2 assessments will not be performed prior to enrollment but it will be assessed retrospectively. Confirmation of TROP2 expression by immunohistology or other methods is not required, but the Sponsor will request tissue specimens from archived materials for determination of TROP2 expression. The patient must have, in the judgment of the investigator, historically documented, incurable, locally advanced or metastatic cancer that are refractory to standard therapies of one of the following types: i. ovarian epithelial cancer, ii. gastric adenocarcinoma, iii. pancreatic adenocarcinoma, iv. triple negative breast cancer, v. bladder cancer. Patient will receive study drug as a single IV infusion at the prescribed dose level at each administration. Cycles will continue until disease progression or unacceptable toxicity. Adverse Events (AE) will be graded according to CTCAE V.5.0. Responses will be evaluated according to RECIST V1.1. The enrollment will began in Mar 2020 in USA sites. Clinical trial information: NCT04152499 .